E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation DOI Open Access
Mingyang Cheng,

Yiyuan Lu,

Jiarui Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 10, 2023

ABSTRACT E3 ubiquitin ligases are very important to regulate antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an ligase, upregulated in the presence of RNA viruses, particularly Influenza A virus (IAV). Notably, overexpression ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai (SeV) H9N2, ablation restores SeV H9N2 infection-mediated transcription IFN-β its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking showed a decreased susceptibility PR8 infections. Mechanistically, interacts with MAVS directly mediates K48-linked polyubiquitination degradation at K297, thereby inhibiting phosphorylation levels TBK1 IRF3, downregulating signaling. These findings establish as critical negative regulator controlling activation signaling describe novel function has not been previously reported. IMPORTANCE IAV is significant zoonotic pathogen causes infections respiratory system. Hosts have evolved multiple strategies defend against However, all host proteins play active defense role. In this study, found ligase regulates manipulating stability. Briefly, degrades MAVS, promoting replication. contrast, deletion expression, upregulating IFN-I responses. Additional research revealed resulting being degraded via ubiquitin-proteasome pathway. reveal, for first time, mechanism which negatively provides potential target anti-IAV drug development.

Language: Английский

VANGL2 alleviates inflammatory bowel disease by recruiting the ubiquitin ligase MARCH8 to limit NLRP3 inflammasome activation through OPTN-mediated selective autophagy DOI Creative Commons
Huaji Jiang, Yingchao Xie, Z. Hu

et al.

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(2), P. e3002961 - e3002961

Published: Feb. 3, 2025

Inflammatory bowel disease (IBD) is a chronic and potentially life-threatening inflammatory of gastroenteric tissue characterized by episodes intestinal inflammation, but the underlying mechanisms remain elusive. Here, we explore role precise mechanism Van-Gogh-like 2 (VANGL2) during pathogenesis IBD. VANGL2 decreases in IBD patients dextran sulfate sodium (DSS)-induced colitis mice. Myeloid deficiency exacerbates progression DSS-induced mice specifically enhances activation NLRP3 inflammasome macrophages. NLRP3-specific inhibitor MCC950 effectively alleviates deficient Mechanistically, interacts with promotes autophagic degradation through enhancing K27-linked polyubiquitination at lysine 823 recruiting E3 ligase MARCH8, leading to optineurin (OPTN)-mediated selective autophagy. Notably, decreased peripheral blood mononuclear cells from results overt sustained inflammation. Taken together, this study demonstrates that acts as repressor inhibiting provides insights into crosstalk between inflammation autophagy preventing

Language: Английский

Citations

1
PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation DOI

Peixiang Zheng,

Z. Hu, Shen Yu-li

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Language: Английский

Citations

1
Expression Profiles of ITGA8 and VANGL2 Are Altered in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) DOI Creative Commons

Nikola Pavlović,

Nela Kelam,

Anita Racetin

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(14), P. 3294 - 3294

Published: July 12, 2024

Kidney failures in infants are mostly caused by congenital anomalies of the kidney and urinary tract (CAKUT), which among most common birth disorders worldwide when paired with cardiac abnormalities. People CAKUT often have severe failure as a result wide range abnormalities that can occur alone or conjunction other syndromic disorders. In this study, we aimed to investigate expression pattern candidate genes alpha-8 integrin (ITGA8) Van Gogh-like 2 (VANGL2) fetal tissues healthy CAKUT-affected kidneys using immunohistochemistry immunofluorescence. We found under circumstances, expressions ITGA8 VANGL2 changed. Additionally, showed is constant during aging, but varies. Moreover, compared normal (CTRL), poorly expressed duplex (DKs) dysplastic (DYS), whereas substantially (DYS) hypoplastic (HYP). These results point potential prognostic indicators for malformations. Further research necessary explore molecular mechanisms underlying differential VANGL2.

Language: Английский

Citations

6
STK39 inhibits antiviral immune response by inhibiting DCAF1-mediated PP2A degradation DOI Creative Commons
Chengfei Zhang, Ping Xu, Yongsheng Wang

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2025, Volume and Issue: 15(3), P. 1535 - 1551

Published: Jan. 1, 2025

Evading host immunity killing is a critical step for virus survival. Inhibiting viral immune escape crucial the treatment of diseases. Serine/threonine kinase 39 (STK39) was reported to play an essential role in ion homeostasis. However, its potential and mechanism infection remain unknown. In this study, we found that promoted STK39 expression. Consequently, overexpressed inhibited phosphorylation interferon regulatory factor 3 (IRF3) production type I interferon, which led replication escape. Genetic ablation or pharmacological inhibition significantly protected mice from infection. Mechanistically, mass spectrometry immunoprecipitation assays identified interacted with PPP2R1A (a scaffold subunit protein phosphatase 2A (PP2A)) activity-dependent manner. This interaction DDB1 CUL4 associated 1 (DCAF1)-mediated degradation, maintained stabilization activity PP2A, which, turn, suppressed IRF3, decreased then strengthened replication. Thus, our study provides novel theoretical basis escape, may be therapeutic target infectious

Language: Английский

Citations

0
Role of nasal microbiota in regulating host anti-influenza immunity in dogs DOI Creative Commons

Jinzhu Geng,

Yuhao Dong,

Hao Huang

et al.

Microbiome, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 27, 2025

Numerous studies have confirmed a close relationship between the pathogenicity of influenza and respiratory microbiota, but mechanistic basis for this is poorly defined. Also, majority these been conducted on murine models, it remains unclear how far findings can be extrapolated from models to other animals. Considering that A virus increasingly recognized as an important canine pathogen, study investigated cross-talk nasal lung tissues mediated by microbes its association with susceptibility in beagle dog model. Using 16S rRNA gene sequencing, combined comparative transcriptomic, anatomical, histological examinations, we viral presence, expression profiles, microbiota cavity after infection beagles antibiotic-induced dysbiosis. Our data showed dysbiosis microbiome exacerbates influenza-induced disease epithelial barrier disruption, impairs host antiviral responses lung. Moreover, dysregulation disturbance microbiota. Further, also identified strain Lactobacillus plantarum isolated significant effect vitro, found activity might associated activation interferon (IFN) pathway modulation impaired autophagy flux induced infection. investigation reveals exerts prominent impact responses, inflammation thresholds, mucosal integrity during Lactobacilli, part may contribute defenses modulating IFN pathways. Collectively, underscores importance homeostasis maintaining health.

Language: Английский

Citations

0
VANGL2 downregulates HINT1 to inhibit the ATM-p53 pathway and promote cisplatin resistance in small cell lung cancer DOI Creative Commons
Jiayi Xie, Huiying Liu,

Chunqian Yang

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: April 8, 2025

Language: Английский

Citations

0
Carpaine ameliorates synovial inflammation by promoting p65 degradation and inhibiting the NF-κB signalling pathway DOI Creative Commons
Hongbo Zhang,

Ziyang Li,

Zhicheng Zhang

et al.

Bone and Joint Research, Journal Year: 2025, Volume and Issue: 14(4), P. 353 - 364

Published: April 16, 2025

Aims Osteoarthritis (OA) is a chronic and debilitating joint disease. Despite its prevalence, especially in ageing obese populations, effective treatments targeting the molecular mechanisms of OA are limited. This study aimed to investigate role carpaine (CP), major alkaloid from Carica papaya leaf, inhibiting articular cartilage destruction synovitis during progression, elucidate underlying mechanisms. Methods CP (purity > 98%) was dissolved dimethyl sulfoxide (DMSO). Various antibodies reagents were sourced Sigma-Aldrich, Abcam, other suppliers. Peritoneal macrophages (pMACs) cultured Dulbecco’s Modified Eagle Medium (DMEM) treated with assess effects on inflammatory cytokine production nuclear factor-kappa B (NF-κB) signalling. A total 40 ten-week-old male C57/BL6 mice underwent destabilization medial meniscus (DMM) surgery induce OA. Post-surgery, (0.5 or 3 mg/kg) vehicle via intra-articular injections for up ten weeks. Cartilage degradation evaluated using Safranin O, Fast Green staining, haematoxylin eosin (H&E) immunohistochemistry, quantitative polymerase chain reaction (PCR). Results treatment significantly reduced degeneration maintained hyaline thickness compared group. Indicators degeneration, such as collagen X (Col X) matrix metallopeptidase 13 (MMP13), markedly decreased CP-treated exhibited lower scores at both five weeks post-DMM surgery. prominently proinflammatory cytokines (interleukin (IL)-1β, IL-6) M1 polarized vitro vivo. impeded NF-κB signalling by promoting p65 through E3 ubiquitin ligase LRSAM1. The defensive effect reversed Lrsam1 small interfering RNA (siRNA), confirming LRSAM1 CP-mediated inhibition. Conclusion acts ‘physiological brake’ activation, thereby mitigating synovial inflammation These findings suggest that could be promising therapeutic strategy Cite this article: Bone Joint Res 2025;14(4):353–364.

Language: Английский

Citations

0
The multifaceted roles of selective autophagy receptors in viral infections DOI
Rui Luo, Tao Wang,

Jing Lan

et al.

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

Selective autophagy is a protein clearance mechanism mediated by evolutionarily conserved selective receptors (SARs), which specifically degrades misfolded, misassembled, or metabolically regulated proteins. SARs help the host to suppress viral infections degrading However, viruses have evolved sophisticated mechanisms counteract, evade, co-opt autophagic processes, thereby facilitating replication. Therefore, this review aims summarize complex of involved in infections, focusing on how exploit strategies regulate autophagy. We present an updated understanding various critical roles pathogenesis. Furthermore, newly discovered evasion employed are discussed and ubiquitination-autophagy-innate immune regulatory axis proposed be crucial pathway control infections. This highlights remarkable flexibility plasticity

Language: Английский

Citations

3
The E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation DOI
Mingyang Cheng,

Yiyuan Lu,

Jiarui Wang

et al.

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 12, 2024

Language: Английский

Citations

2
The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti‐T. Gondii Immunity and Tumor Immunotherapy DOI Creative Commons
Zhiqiang Hu,

Yufen Zhang,

Yingchao Xie

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(32)

Published: June 21, 2024

Abstract Toxoplasma gondii ( T. )‐associated polymorphic effector proteins are crucial in parasite development and regulating host anti‐ immune responses. However, the mechanism remains obscure. Here, it is shown that dense granules 4 (GRA4) restricts IFN‐I activation. Infection with Δ gra4 mutant strain induces stronger responses poses a severe threat to health. Mechanistically, GRA4 binds phosphorylated TBK1 promote TRIM27‐catalyzed K48‐ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading autophagic degradation. Furthermore, an avirulent (ME49Δ ompdc / ) constructed for tumor immunotherapy due ability enhance production. Earlier vaccination ME49Δ confers complete resistance compared classical treatment. Notably, specific CD64 + MAR‐1 CD11b dendritic cell subset, thereby enhancing T anti‐tumor Overall, these findings identify negative role of modulating signaling suggest can be potential target vaccines immunotherapy.

Language: Английский

Citations

1